Majority of cancer patients die of metastases originating from disseminated tumor cells (DTCs), years and decades after treatment, possibly because the DTCs can survive in a quiescent or dormant state and evade therapies. Our long-term goal is to understand the biology of dormant DTCs with the goal of maintaining this state or converting proliferative residual DTCs into dormancy. As we stand cancer research has achieved limited success in stopping metastasis even with the most sophisticated understanding of oncogene biology and chemo/radiotherapy. Further, stopping DTCs awakened from dormancy may not be effective either, as we found that forcedly reactivating dormant DTCs causes rapid progression to lethal multiorgan metastasis. Our R01 competitive renewal breaks new ground in the mechanistic understanding of dormancy and in the design of rational therapies to induce and maintain dormancy of systemic residual cancer. This is significant because by modulating DTC quiescence it shifts the paradigm of metastasis treatment and it addresses unmet clinical needs. Our hypothesis is that naturally occurring niche signals instruct proliferative DTCs to enter dormancy by activating quiescence programs. We will exploit these signals to induce and maintain dormancy of DTCs. We discovered that solitary DTCs establish a reciprocal crosstalk with the microenvironment in dormancy-permissive (bone marrow, BM) or -restrictive (lung) target organs. We identified alltrans retinoic acid (atRA), TGF?2 and BMP7 signaling as BM cues that induce a high p38/ERK activity ratio and dormancy of proliferative DTCs. We also identified the transcription factors DEC2 and NR2F1 as the executors of the dormancy program and, importantly, systemic BMP7 treatment restores this program and suppresses lung metastasis after surgery. We also found that the dormancy markers we identified can pinpoint dormant DTCs in prostate cancer patients asymptomatic for 7-18 years. This validation prompted the design of a reprogramming therapy using the DNA demethylating agent 5azacytidine (AZA), atRA or specific RAR? and RAR? agonists to reprogram proliferative DTCs into stable induced Dormant Cancer Cells (iDCCs). In this continuation, we propose to 1) study how atRA, TGF?2 and BMP7 induce DTC dormancy and identify the stromal cells that produce the dormancy cues in the BM, 2) study how DEC2 and NR2F1 regulate an epigenetic program of dormancy and 3) optimize the reprogramming protocol combining AZA with specific RAR?/? agonists and new MEK1/2 inhibitors to maintain residual disease, chronic, asymptomatic and nonlife threatening. The biology we uncovered supports that the drugs used to generate iDCCs may be repurposed as a much needed metastasis preventive strategy by inducing and maintaining DTC dormancy. If successful, clinical trials scenarios may be available to test if iDCC induction may suppress metastasis.